单克隆抗体生产过程中二硫键还原成因及预防方法

单克隆抗体生产过程中二硫键的还原是生物制药领域中的一个常见技术难题,可产生低分子量碎片,影响产品质量,导致蛋白纯度降低、稳定性下降,影响药物的安全性和有效性。抗体二硫键还原实质上是由细胞内的硫氧还蛋白系统和谷胱甘肽系统引起的可逆氧化还原反应,并与具体生产过程参数有关。近年来,随着抗体药物和哺乳动物细胞培养工艺规模的发展,二硫键还原问题频繁发生。为解决此问题,研究人员不断尝试并建立了多种预防方法以保证产品质量。概述了抗体二硫键结构、二硫键还原的主要成因及生产过程中的形成因素,重点阐述了消除或减缓抗体二硫键还原的方法、对策,并列举了几种可行的过程分析技术,以期为单克隆抗体药物生产制造工艺的进一步优化提供参考。

Root Cause and Prevention of Monoclonal Antibody Disulfide Bonds Reduction During Biopharmaceutical Manufacturing Process

Monoclonal antibody disulfide bonds reduction has been a common issue in biopharmaceutical process, which could produce low-molecular weight fragments, affect product quality, and lead to decreased protein purity and stability. Moreover, it could also affect the safety and effectiveness of drugs. Antibody disulfide bonds reduction is a reversible redox reaction caused by intracellular thioredoxin system and glutathione system, and is related to the specific production process. In recent years, with the development of antibody drugs and mammalian cell culture scale, disulfide bonds reduction is observed more frequently. To solve this problem, scientists have been constantly developing mitigation strategies to ensure the product quality. In this paper, the antibody disulfide bonds structure, cause of disulfide bonds reduction and influencing factors in manufacturing process were summarized. It is focused on the prevention methods in the manufacturing process. Additionally, several feasible process analysis techniques are listed so as to provide reference for the further development of monoclonal antibody drugs in manufacturing.